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An early morning test explosion of the first atomic plutonium bomb is planned at a military site in Desert Rock, Nevada. When the chain reaction for the charge fails its cycle and does not detonate as expected, Lt. Glenn Manning receives orders to keep his men in the protective trench as an explosion is still imminent but its timing is now unknown. Moments later, an unidentified small civilian aircraft crash lands near the bomb site, and Manning leaps from the trench and runs into the detonation area to rescue the pilot. Once in the detonation area, the bomb goes off and Manning is caught in an atomic blast that burns him and immediately disintegrates his clothes and hair.

Surviving the blast but suffering from third-degree burns over almost his entire body, Manning is treated by specialist Dr. Paul Linstrom and military scientist Dr. Eric Coulter at the base hospital. Glenn's fiancée, Carol Forrest, who was supposed to have been married to him that very night in Las Vegas, anxiously awaits a prognosis, but Linstrom refrains from telling her that the consensus is that Glenn will not survive.

The next morning, however, Drs. Linstrom and Coulter are stunned to discover that Glenn’s burns have completely healed, without so much as scarring. Linstrom and Coulter are concerned over the incredible recuperation and begin analyzing the details of Glenn’s unusual case. That same evening, Forrest is upset when Glenn’s security officer informs her that she is prohibited from seeing Glenn again, and she later learns that he has been moved out of the hospital to another facility - an army rehabilitation and research center in Summit, Nevada. Forrest drives out and is admitted entry, and after overhearing Linstrom and Coulter discussing Glenn’s case, Carol lets herself into Glenn’s room. She faints in horror when she sees him lying on a large pad on the floor, mutated into a giant of about 16 feet tall.

Later, Linstrom tells Carol that it is believed that Glenn's exposure to the plutonium blast has caused his old cells to stop dying and his new cells to multiply at an accelerated rate, resulting in his growing proportionately eight feet in height a day. Linstrom admits that he and Coulter do not know if they can stop Glenn's growth – and that if they don’t, he will continue to grow until he dies - but assures her that they will not stop their research.

The following day, Glenn awakens after unsettling dreams of his past with Carol, his time in the Korean War, and the night he was injured in the plutonium blast. Upon realizing his massive size, Glenn is at first frightened, then deeply disturbed. Carol sees him the next morning to comfort him, but he – now over 22 feet tall – is distant and morose. While the public knows that Glenn survived the explosion, the military has kept the truth of his condition from the media.

As Glenn’s body continues to increase in size, Linstrom orders him moved to a tent large enough to provide shelter and recommends that Carol spend time with him. However, despite Carol's encouragement, Glenn is angry and bitter. Linstrom eventually reveals that it has been learned that Glenn's heart is growing at only half the rate of his body and soon will be unable to support his enormous size – that he will die in a matter of days. That night, Carol and Glenn argue over his continuing despair and pessimism.

The following morning as Coulter reports to Linstrom that he may have found a solution to Glenn's growth, it is discovered that Glenn has disappeared. Although two motorists come across him on Highway 93, the military, headed by Col. Hallock, conducts a ten-mile-wide search for the now over 50-foot tall Glenn, but with no results. When Carol asks Linstrom if she can help in their search for Glenn, he cautions her that Glenn's condition may be affecting his mind. Later, Coulter declares that he has created a special syringe filled with a serum for Glenn's bone marrow that will stop his growth. Hallock then briefs the military squads on their expanding search, which will also be conducted by air.

Meanwhile, the local news relays that 'a giant man' has been spotted approaching Las Vegas. As the military heads toward Las Vegas, Glenn, now over 60 feet tall and psychologically confused, is drawn to the Las Vegas strip. His appearance panics the local populace, as he breaks out a window in the Riviera Hotel while seeing a woman bathing inside, and wreaks havoc on the Royal Nevada, the Silver Slipper and the Tropicana. At the Sands hotel he picks up a convertible and hurls it at the crowd, just before smashing the Sands’ 56-foot neon sign. When the police become alarmed by Glenn's behavior, they disobey military orders and begin firing at him, thus enraging Glenn, who then moves toward Fremont Street and completely destroys the Pioneer Club’s Vegas Vic sign and heads toward Boulder Dam as military helicopters track his movements.

Linstrom, Carol and Coulter, who are also traveling by helicopter, attempt to intercept Hallock's troops. After landing at the dam, Coulter and Linstrom immediately take the enormous syringe and plunge it into Glenn's ankle. Glenn is startled, then outraged and, removing the syringe, mercilessly spears Coulter with it. Glenn then picks up Carol and starts across the dam. Using a bullhorn to amplify his message, Linstrom pleads with Glenn to spare Carol and although he is utterly disoriented, Glenn complies. When Glenn reaches the middle of the dam, Hallock orders his men to fire on him and Glenn tumbles into the Colorado River to his death.

The film and its sequel were featured and riffed on the cult classic mocking show Mystery Science Theater 3000; actor Mike Nelson portrayed the title character twice in the mid-movie host sections of the show's season 3, episodes 9 and 19. On episode 9, the character seems more aggressive to Joel and the bots when the Satellite of Love hit him and nearly proceeds to attack the trio after Tom Servo unintentionally insulted Glen before leaving when suffering from brief heart attack, as portrayed in the movie.

The film was parodied on an episode[which?] of Robot Chicken when a large bald giant, wearing a sarong as a diaper, is struck in the crotch with a wrecking ball as he terrorizes a city, as part of the "Ode to the Nut Shot" sketch.